Fisetin Attenuates Cellular Senescence Accumulation During Culture Expansion of Human Adipose-Derived Stem Cells.

Mesenchymal stem cells (MSCs) have long been viewed as a promising therapeutic for musculoskeletal repair. However, regulatory concerns including tumorgenicity, inconsistencies in preparation techniques, donor-to-donor variability, and the accumulation of senescence during culture expansion have hindered the clinical application of MSCs. Senescence is a driving mechanism for MSC dysfunction with advancing age. Often characterized by increased reactive oxygen species, senescence-associated heterochromatin foci, inflammatory cytokine secretion, and reduced proliferative capacity, senescence directly inhibits MSCs efficacy as a therapeutic for musculoskeletal regeneration. Furthermore, autologous delivery of senescent MSCs can further induce disease and aging progression through the secretion of the senescence-associated secretory phenotype (SASP) and mitigate the regenerative potential of MSCs. To alleviate these issues, the use of senolytic agents to selectively clear senescent cell populations has become popular. However, their benefits to attenuating senescence accumulation in human MSCs during the culture expansion process have not yet been elucidated. To address this, we analyzed markers of senescence during the expansion of human primary adipose-derived stem cells (ADSCs), a population of fat-resident MSCs commonly used in regenerative medicine applications. Next, we used the senolytic agent fisetin to determine if we can reduce these markers of senescence within our culture-expanded ADSC populations. Our results indicate that ADSCs acquire common markers of cellular senescence including increased reactive oxygen species, senescence-associated ß-galactosidase, and senescence-associated heterochromatin foci. Furthermore, we found that the senolytic agent fisetin works in a dose-dependent manner and selectively attenuates these markers of senescence while maintaining the differentiation potential of the expanded ADSCs.

A Roadmap to Heart Regeneration Through Conserved Mechanisms in Zebrafish and Mammals.

PURPOSE OF REVIEW: The replenishment of lost or damaged myocardium has the potential to reverse heart failure, making heart regeneration a goal for cardiovascular medicine. Unlike adult mammals, injury to the zebrafish or neonatal mouse heart induces a robust regenerative program with minimal scarring. Recent insights into the cellular and molecular mechanisms of heart regeneration suggest that the machinery for regeneration is conserved from zebrafish to mammals. Here, we will review conserved mechanisms of heart regeneration and their translational implications. RECENT FINDINGS: Based on studies in zebrafish and neonatal mice, cardiomyocyte proliferation has emerged as a primary strategy for effecting regeneration in the adult mammalian heart. Recent work has revealed pathways for stimulating cardiomyocyte cell cycle reentry; potential developmental barriers for cardiomyocyte proliferation; and the critical role of additional cell types to support heart regeneration. Studies in zebrafish and neonatal mice have established a template for heart regeneration. Continued comparative work has the potential to inform the translation of regenerative biology into therapeutics.